Acridine compounds and process of making same



Patented Apr. 22, 1947 A CRllDKNE COMPOUNDS AND PROCESS OF MAKING SAMEJoseph H. Burckhalter, Detroit, Albert L. Rawlins,

Grosse Pointe Woods, Frank H. Tendick, Grosse Pointe Park, Eldon M.Jones, Grosse' Pointe Vfoods, and Walter F. Holcomb, Detroit, Mich,assignors to Parke, Davis & Company, Detroit, Mich, a corporation ofMichigan No Drawing. Application February 9, 1945, Serial N0. 577,150

13 Claims.

This invention relates to a class of new basically substituted acridinecompounds having the general formula for the free base NE T wherein R1and R2 are substituents selected from the class consisting of hydrogen,lower alkyl, lower alkoxy, chlorine, bromine and CN, and (B3) representsn substituents R3, where n has one of the values 0, 1, 2 or 3 and R3 isa substituent of the class consistirr of hydrogen, lower alkyl,chlorine, bromine, CN and -NO2. The group A has the formula where R4 maybe hydrogen, lower alkyl or lower hydroxyalkyl and R5 may be lower alkylor lower hydroxyalkyl, R4 and 35 may be taken together with N to form aheterocyclic ring consisting of a member of the class piperidine,morpholine, thiomorpholine, pipers-zine, pyrrolidine and pyr role.

These new compounds are useful therapeutic agents and, in general, theyare characterized by their toxicity to plasmodia. These new compoundsmay be used in the form of their free bases or in the form of theirsalts with organic or inorganic acids such as hydrochloric acid,sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, lactic acid,tartaric acid, gluconic acid, citric acid and alkyl sulfonic acids or asthe insoluble salt of methylene disalicylic acid.

The new acridine compounds of the present invention may be prepared bycondensing equimolar portions of a substituted aryl amine and aQ-haloacridine in a suitable solvent. The reaction may be carried out inthe presence of alkaline, neutral or acidic media, and the reaction maybe graphically represented as follows.

where R1, R2, R3, A and n have the values previously given and Xrepresents a halogen such as chlorine or bromine. We prefer to carry outthe condensation in the presence of a dilute or concentrated organicacid or a dilute inorganic acid.

Another method for the preparation of these heterocyclic amines of thepresent invention, which is, in effect, a variation of the above methodusing an acidic medium, involves the reaction of the substituted arylamine and the 9-haloacridine in phenol. The desired product may beprecipitated from an ether suspension of the reaction mixture lay theaddition of hydrogen chlo- O\N/OVR2 l lHz l J n I I W 7R1 The followingexamples illustrate ourinventionwithout restricting itthereto: I

Phenol Ezrample 1.2-meth0:cy-6-chloro-9-(4'-diethylaminomethylanilzno)-acridine dihyclrochloride CHzCH:

CHQN

I CHGHa omo- A N/ 01 -2no1 A mixture consisting of 9.6 g. (0.054 mole)of l-(diethylaminomethyl) aniline [Bull. soe'chim; (4) 19', "339'(1916)] and 13 .9 g. (0.05 mole). of 2-methoxy-6,9-dichloroacridine in100 cc. of methanol is treated with hydrogen chloride in methanol untilthe pH of the mixture is about 4. The acidified reaction mixture isheated on a steam bath for fifteen minutes, cooled and allowed to standovernight. The crystalline clihydrochloride is removed by filtration,washed with acetone and recrystallized from methanol; M. P. 265' G. dec.

Example 2.2 methoxy 6 chloro 9 (2 diethyldminomethylkmtliho -aeridinedzhydrochloride (Ill CHzCHa I C1 CHzN. N

C Ha CH3 C HEN- C H CH 3 A mixtureconsisting of 7.5 g. (0.042 mole) of 2(diethylaminomethyl) aniline I [Bull. Soc. Chim, (4), 19, 339 (1916)]and 11.8 g. (0.042 mole) of 2-methoxy-6,9-dichloroacridine in 100 cc. ofmethanol is treated .with hydrogen hydrochloride in methanol until thepH of the mixture is about 4-. The acidified reaction mixture is heatedon the" steam bath for two hours, cooled and the crude product removedby filtration. The product is purified further by washing With acetoneand recrystallization from methanol.

Example 3.-2 methoscy 6 chloro 9 (3 diethylaminomethylanilino)-acridinedz'hydrochloride 25. 1 g. (0.1 mole) of 3-(diethylaminomethyD- anilinedihydrochloride [Bull. Soc. Chim, (4) 19, 339 (1916)] and 25.03 g. (0.09mole) of Z-methoxy6,9-dichloroacridine suspended in 300 cc. of absoluteethanol is refluxed for two hours. The mixture is cooled, the crudedihydrochloride collected and recrystallizedfrom methanol; M. P. 278 C.

Example 4.2 methozry 6 chloro 9 (3 diethanolaminomethylanilino)-acridine dihydrochloride CH2CH2OH The pH of a mixture consisting of 7.5g. (0.36 mole) of 3-(diethanolaminomethyl)aniline and 9.9 g. (0.036mole) of Z-methoxy-6,9-dichloroacridine in cc. of methanol is adjustedto 4 by the addition of hydrogen chloride in methanol. The resultingmixture is heatedon a steam bath for two hours, cooled and thecrystalline dihydrochloride collected. The crude product is washed withacetone and recrystallized from methanol.

Example 5.-2 methomy 6 chloro 9 (3" N pipericlylmethylanilino) acrz'dmedihydro- OH2OH2OH CH2 G H:

A mixtureconsisting of'6.5 g. (0.025 mole) of 3 (N piperidylmethyl)aniline dihydrochlorideand 6.85 g. (0.025 mole) of 2-methoXy-6,9-dichl0-roacridine in cc. of methanol is refluxed on a' steam bath for twohours. The mixture is cooled,

the crystalline dihydrochloride collected, washed with acetone andrecrystallized from methanol.

Example 6.2 methoxy 6 ch loro 9 (3 N morpholznylmethylanilino) acridinedihydrochlorz'de OHaCHn Q onion, X CHaO- CHaN O C H: C H:

A mixture consisting of 8.5 g. (0.032 mole) of 3- (N-morpholinylmethyl)aniline dihydrochloride and 9.0 g. (0.032 mole) of2-methoxy-6,9-dichloroacridine in 125 cc. of methanol is heated on asteam bath for two hours. The mixture is cooled and the crystallinedihydrochloride is removed by filtration. The crude product is washedwith acetone and recrystallized from methanol.

Example 7.2 methoxy 6 chloro 9 (4 Nthz'omorpholinylmethylanilino)acridine dihydrochloride CHZN CHzCH2CHaCH:

CHzN s CHzOH:

A mixture consisting of5 g. (0.018 mole) oi. 4 -(Nthiomorpholinylmethyl) aniline dihydrochloride and 4.95 g. (0.018 mole)of 2-methoxy- 6,9-dichloroacridine in 75 cc. ofmethanol is refluxed fortwo hours, cooled and the crystalline product removed by filtration. Thecrude dihydrochloride is Washed with acetone and recrystallized frommethanol.

Example 8.-2-methoa'y-6-chloro 9 -(2'- chloro-5-diethylaminoethylanilino)acridine dihydrochloride CHqCHz CHzO CH2NCHaCHa NHn CH2N onao- A OHzCHz \N -c1 mm A mixture consisting of 7.5 g.(0.026 mole) of 2-chloro-5- (diethylaminomethyl aniline dihydrochlorideand 7.3 g. (0.026 mole) of 2-methoxy- 6,9-dichloroacridine in cc. ofmethanol is heated on a steam bath for two hours. The mixture is cooled,the crystalline dihydrochloride removed by filtration, washed withacetone and purified by recrystallization from methanol.

Example 9.--2-metho:cy-6-chloro-9- (Z-N-piperidyZmethyl-5'-chloroanilino)acridine dihz drochloride CHnCHn -b-CI CH2N CH2 N g I NBZ CHzC z 01 I 6 CH 0 I CHZOHQ CH2N CH2 N C] CHzC 2'ZHCI A mixture consisting of 7.5 g. (0.025 mole) of2-(N-piperidylmethyl)-5*ch1oroani1ine and 7.0 g. (0.025 mole) of2-methoxy-6,9-dichloroacridine in cc. of methanol is refluxed on a steambath for two hours. The mixture is cooled, and the crude dihydrochlorideremoved by filtration and washed with acetone. The product is furtherpurified by recrystallization from methanol.

Example 1 0.2 -methoxy-6-brom0-9- (2-diethylaminomethyl-5 -m'tram'lino)acridine dihydrochloride The pH of a mixture consisting of 5 g. (0.022mole) of 2-(diethylaminomethyl)-5-nitraniline and 7.2 g. (0.022 mole) of2-methoxy-6-bromo-9- chloroacridine in 125 cc. of methanol is adjustedto about 4 by the addition of hydrogen chloride in methanol. Theresulting acidified mixture is heated for two hours on a steam bath,cooled and the crystalline dihydrochloride removed by filtration. Thecrude product is Washed with acetone and recrystallized from methanol.

Example '115-2-methoxy 6-cycmo-9-(3'-diethylaminomethylcmilino) acridlnedihydroehloride A mixture consisting of 6.5 g. (0.026 mole) of 3-(diethylaminomethyl) aniline dihydrochloride and 7.0- g. (0.026 mole) of2-methoXy-6-cyano-9- chloroacridine in 125 cc. of methanol is heated forone hour on the steam bath, cooled and the crystalline product removedby filtration. The crude Z-rnethoxy-G-cyano 9-(3-diethylaminomethylanilino) acridine dihydrochloride is washed withacetone and recrystallized from methanol.

Example 1 2.2 -methoa:y-6-cyano-9- (3' -N-piperidylmethylanilino)acrzdz'ne dihydrochloride CHzOHz 011.0 A cmN om N CHzCHS N l N112 OH 0-A omen.

A mixture consisting of 6.85 g. (0.026v mole) of 3-(N'-piperidylmethyl)aniline dihydrochloride and "I g. (0.026 mole) of 2-methoxy-6-cyano-9-chloroacridine in 125 cc. of methanol is heated for one hour on thesteam bath, cooled and the crystalline product removed by filtration.The crude Z-methoxy-G-cyano 9 (3'- N piperidyl-- methylanilino) acridinedihydrochloride is washed with acetone and recrystallized from methanol.

Example 13.2-meth0a:w-6-cyano-9-(2-bromo5'-N-piperidylmethylanilino)acridine dihydrochloride /CH2C2 01130 A OHN/CH2 (31120112 CN Br N NH: -2Ho1 CHzCHg 11\ \CF C 21* U2 ciao A CH2CH2 I\N/ CI\ -2nc1 A mixture consisting of 7.0 g. (0.02 mole) of 2- bromo 5(N-piperidylmethyl) aniline dihydrochloride and 5.5 g. (0.02 mole) of2-methoX-y-6- cyano-9-chloroacridine in 125 cc. of methanol is heated ona steam bath for two hours. The mixture is cooled, and the crystallinedihydroehloride removed by filtration. The product is purified furtherby washing with acetone and recrystalli- 5 zation from methanol.

Example 14.2-methyl-6-chlor0-9- (2-chloro-5-dieth'ylaminomethylanilino)acridine dihydrochloride 01 10 A /oH.oH3

on CH2N\ CHzCHa \N o1 01 i5 II\TH2 -2HCl 01 0H 0H I I 2 a CHzN 0H701110113 Cl -2HO1 N/ A mixture consisting of 6.0 g. (0.021 mole) of 2chloro 5-(diethylarninomethyl) aniline dihydrochloride and 5.5 g. (0.021mole) of 2-methyl- 6,9-dichloroacridine in 125 cc. of methanol isrefiuxed for two hours on a steam bath. The mixture is cooled, thecrystalline dihydroehloride collected, washed with acetone andrecrystallized from methanol.

Example 15.2,6 dlchloro 9-(3-N-'piperidylmethylamlino) acridinedzhydrochlorz'de A mixture consisting of 6 g. (0.023 mole) of 3- Npiperidylmethylaniline dihydrochloride and 5.65 g. (0.023 mole) of6,9-dichloroacridine in 100 cc. of methanol is refluxed for two hours.

The mixture is cooled, the crude dihydrochloride collected andrecrystallized from methanol. The intermediate substitutedaminomethylanilines can be prepared by halogenation of the correspondingnitrotoluene with chlorine or 0 bromine in the presence of light or withhalogenating agents, such .as, sulfuryl chloride in the presence oforganic peroxides; reacting the hitrobenzyl halide with an appropriateprimary or secondary amine and reduction of the nitro group by knownmethods.

These substituted aminomethylanilines can also be prepared from anappropriately substituted benzyl alcohol by conversion of the aliphatichydroxyl group to halogen; reaction of 7 the .halomethylaryl with anappropriate primary or secondary amine; nitration of the substitutedaminomethylbenzene and reduction of the nitro group by known methods.

The various intermediate 9 halogenated acridines can be prepared bymethods similar to 9 those described by Magidson and Travin EJ. Gen.Chem. (U. S. S. R.), 11, 243-53 (1941)] and also by D. R. P. 565,411.

Although the above examples relate to the preferred products of theinvention wherein the amino radical of group A of the general formula isentirely substituted and has no amino hydrogen atom, the invention inits broader aspects also embodies the preparation of compounds where R4is hydrogen and the group A has the formula R5 For example, thecompound, 2-methoxy-6- chloro 9-(4'-ethylaminomethylanilino) acridinedihydrochloride can be prepared by the same procedure as described inExample 1 by reacting the compound of the formula CHzN CHsCHe NHz withthe halogenated acridine compound having the formula Attention is calledto certain of applicants copending applications which show and claimcompounds having a structure somewhat resembling the compounds hereindisclosed and claimed but difiering therefrom in the fact that theycontain hydroxylic substituents in the anilino radical. Among ourcopending applications relating *to substituted amino-methylanilinoacridine compounds also containinghydroxylic substituents in the anilinoradical are the following: Serial No. 539,990, filed June 12, 1944;Serial No. 571,961, filed January 8, 1945; Serial No. 629,713, filedNovember 19, 1945.

What we claim as our invention is:

1. A compound of the class consisting of a free base and its acidaddition salts, the free base of said compound having the formulawherein R1 and R2 are substituents selected from the class consisting ofhydrogen,lower alkyl, lower alkoxy, chlorine, bromine and --CN; (R3) 1;repre- A. Il ab.

sents n substituents R3, where n has one of the where R4 is a member ofthe class consisting of hydrogen, lower alkyl and lower hydroxyalkyl,R5-

is a member of the class consisting of lower alkyl and lowerhydroxyalkyl and further members in which R; and R5 taken together withN form a heterocyclic ring consisting of a member of the classpiperidine, morpholine, thiomorpholine, piperazine, pyrrolidine andpyrrole.

2. A compound of the class consisting of a free "base and its acidaddition salts, the free base of said compound having the formulawherein R1 and R2 are substituents selected from the class consisting ofhydrogen, lower alkyl, lower alkoxy, chlorine. bromine and --CN; (R3) 11represents n substituents R3, where 'n has one of the values 0, 1, 2 and3 and R3 is a substituent of the class consisting of lower alkyl,chlorine,

bromine, -CN and NO2; the formula has the formula R4 CH:N/

group A in said CHaCH:

4. A compound having the formula,

CHzCHa 5. A compound having the formula,

OHQO

' CHzCH:

6. The process which consists in reacting the primary amino group of acompound having the formula with a Q-halcgenated acridine compound ofthe formula,

X Hr thereby forming hydrogen halide and a compound having the formula,

l T E 1 -(R)n J 3 R? g where X is a member of the class consisting of Cland Br, wherein R1 and R2 are substituents selected from the classconsisting of hydrogen, lower alkyl, lower alkoxy, chlorine, bromine andCN; (B3) represents n substituent-s R3, wher n has one of the values 0,1, 2 and 3 and R3 is a substituent of the class consisting of loweralkyl, chlorine, bromine, --CN and NOz; the group A has the formula RaornN where Brand R represent members of the class consisting of loweralkyl and lower hydroxyalkyl and further members in which R4 and R5taken together with N form a heterocyclic ring consisting of a member ofthe class piperidine, morpholine, thiomorpholine, piperazine,pyrrolidine and pyrrole,

7. The process which consists in reacting a compound having the formulaNH: J

with a 9-halogenated acridine compound of the formula,

in the presence of an acid of the class consisting of concentrated anddilute organic acids and dilute mineral acids thereby forming hydrogenhalide and a compound having the formula,

where X is a member of the class consisting of Cl and Br, wherein R1 andR2 are substituents selected from the class consisting of hydrogen,lower alkyl, lower alkoxy, chlorine, bromine and CN; (Rah represents nsubstituents R3, where n has one of the values 0, 1, 2 and 3 and Rs withan acridine compound having the formula,

I \N o1 in the presence of an acid of the class consisting of dilute andconcentrated organic acids and dilute inorganic acids thereby obtaininga compound having the formula,

HiN

omcm

CHaO- 9. The process which consists in reacting a compound having theformula CHzCHa CHzN c CHzCHs C1 with an acridine compound having theformula,

o1 c330 A \N CN in the presence of an acid of the class consisting ofdilute and concentrated organic acids and dilute inorganic acids therebyobtaining a compound having the formula,

0 Hz 0 Ha on N cmo- A 2 CHZCHJ Cl N .2HO1

10. The process which consists in reacting a compound having the formulaCHzCHz CHzC 2 NH: with an acridine compound having the formula,

in the presence of an acid of the class consisting of dilute andconcentrated organic acids and dilute inorganic acids thereby obtaininga compound having the formula,

A H N CHQCH:

CHzCi 1 A compound of the class consisting of a free base and its acidaddition salts, the free base of said compound h aving .the formula,

CHQCHI! CHzN CHZCH:

I CHzCHa OHzN CH2CHa 13. A compound of the class consisting of a. freebase and its acid addition salts, the free base of said compound havingthe formula,

CHzCHz OHzOHa JOSEPH H. BURCKHALTER. ALBERT L. RAWLJNS. FRANK I-I.TENDICK.

ELDON M. JONES. WALTER F. HOLCOMB.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS Name Date 35 Number Mietzsch et a1. Apr. 5, 1938

